Integration-free induced pluripotent stem cells model genetic and neural developmental features of Down Syndrome etiology

Briggs, James A., Sun, Jane, Shepherd, Jill, Ovchinnikov, Dmitry A., Chung, Tung-Liang, Nayler, Sam P., Kao, Li-Pin, Morrow, Carl A., Thakar, Nilay Y., Soo, Set-Yen, Peura, Teija, Grimmond, Sean and Wolvetang, Ernst J. (2013) Integration-free induced pluripotent stem cells model genetic and neural developmental features of Down Syndrome etiology. Stem Cells, 31 3: 467-478. doi:10.1002/stem.1297


Author Briggs, James A.
Sun, Jane
Shepherd, Jill
Ovchinnikov, Dmitry A.
Chung, Tung-Liang
Nayler, Sam P.
Kao, Li-Pin
Morrow, Carl A.
Thakar, Nilay Y.
Soo, Set-Yen
Peura, Teija
Grimmond, Sean
Wolvetang, Ernst J.
Title Integration-free induced pluripotent stem cells model genetic and neural developmental features of Down Syndrome etiology
Journal name Stem Cells   Check publisher's open access policy
ISSN 1066-5099
1945-4732
Publication date 2013-03
Sub-type Article (original research)
DOI 10.1002/stem.1297
Volume 31
Issue 3
Start page 467
End page 478
Total pages 12
Place of publication Lansing, MI, United States
Publisher Marsland Press
Collection year 2014
Language eng
Abstract Down syndrome (DS) is the most frequent cause of human congenital mental retardation. Cognitive deficits in DS result from perturbations of normal cellular processes both during development and in adult tissues, but the mechanisms underlying DS etiology remain poorly understood. To assess the ability of induced pluripotent stem cells (iPSCs) to model DS phenotypes, as a prototypical complex human disease, we generated bona fide DS and wild-type (WT) nonviral iPSCs by episomal reprogramming. DS iPSCs selectively overexpressed chromosome 21 genes, consistent with gene dosage, which was associated with deregulation of thousands of genes throughout the genome. DS and WT iPSCs were neurally converted at >95% efficiency and had remarkably similar lineage potency, differentiation kinetics, proliferation, and axon extension at early time points. However, at later time points DS cultures showed a twofold bias toward glial lineages. Moreover, DS neural cultures were up to two times more sensitive to oxidative stress-induced apoptosis, and this could be prevented by the antioxidant N-acetylcysteine. Our results reveal a striking complexity in the genetic alterations caused by trisomy 21 that are likely to underlie DS developmental phenotypes, and indicate a central role for defective early glial development in establishing developmental defects in DS brains. Furthermore, oxidative stress sensitivity is likely to contribute to the accelerated neurodegeneration seen in DS, and we provide proof of concept for screening corrective therapeutics using DS iPSCs and their derivatives. Nonviral DS iPSCs can therefore model features of complex human disease in vitro and provide a renewable and ethically unencumbered discovery platform.
Keyword Induced pluripotent stem cells
Disease modeling
Down syndrome
Trisomy 21
Neural development
Gene dosage
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 28 Mar 2013, 10:19:30 EST by Mrs Louise Nimwegen on behalf of Aust Institute for Bioengineering & Nanotechnology